CN1850806A - Method for preparing secnidazole - Google Patents
Method for preparing secnidazole Download PDFInfo
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- CN1850806A CN1850806A CN 200610050887 CN200610050887A CN1850806A CN 1850806 A CN1850806 A CN 1850806A CN 200610050887 CN200610050887 CN 200610050887 CN 200610050887 A CN200610050887 A CN 200610050887A CN 1850806 A CN1850806 A CN 1850806A
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Abstract
This invention relates to secnidazole [1-(2-hydroxy group propyl)-2-methyl-5- nitro imidazole] preparation method, it belongs to chemical pharmacy technique field. 2-methyl-5-nitro imidazole and 1-chlorine-2-propyl alcohol are materials, dry acid gas is let in to dissolve solid, then heated, distilled and recover 1-chlorine-2- propanol, pH is adjusted by sig water and cooled to 0 degree centigrade. Then it is filtrated, unreacted 2-methyl-5-nitro imidazole is recovered, filtrate pH value is adjusted to alkality, and then secnidazole crude is got after filtration. Reaction temperature is 85-95 degrees cenrigrade, reaction time is 6.0-7.5 hours, mol ratio of 2-methyl-5-nitro imidazole and 1-chlorine-2-propyl alcohol is 1:3.25-5.30. Compering to existing technique, the reaction preoceudre is only one step, generating period is shortened, and operation is simplified. Reaction whole yield is improved from less than 50 percent reported from document to 56-60 percent, and material mass using is reduced, so generating cost is reduced, generating safty is also improved.
Description
Technical field
The present invention relates to the preparation method of a kind of secnidazole [1-(2-hydroxypropyl)-2-methyl-5-nitro imidazoles], belong to technical field of pharmaceutical chemistry.
Background technology
Secnidazole has the structure shown in general formula I, is anti-efficiently amoeba of 5-nitro glyoxaline and anti-trichomonal medicine.The clinical trichomoniasis such as various acute and chronic liver sausage loeschiasiies and urethra, vagina, male prostate that are used for the treatment of also are used for the treatment of giardiasis and partes corporis humani position anaerobic infection.
General formula I
About the preparation method of secnidazole, bibliographical information roughly has following several at present:
1, Rhone-poulec S.A report (French Patent 1427627 and French Patent M3270) is dissolved in 2-methyl-5-nitro imidazoles (1mol) in 85% the formic acid (7.88 parts), be cooled to-14 ℃, drip propylene oxide (5mol), remove formic acid after the reaction under reduced pressure, reclaim unreacted 2-methyl-5-nitro imidazoles, transfer pH to obtain crude product, get pure product secnidazole, yield 47.94% after toluene is refining.
2, German Patent 2107423, and English Patent 1278758 reports are suspended in glyoxal ethyline, monochloroacetone, Anhydrous potassium carbonate in the acetone, get product through nitrated, sodium borohydride reduction, total recovery 3.62%.
3, English Patent 1278757,1278758 reports are solvent with glyoxal ethyline and propylene oxide reaction with ethanol, make intermediate 1-(2-hydroxypropyl)-glyoxal ethyline; Go protection to obtain product, total recovery 6.25% through Acetyl Chloride 98Min. acetylize protection hydroxyl, nitrated, hydrolysis again.
4, the WO9113877 report is dissolved in 1-acetoxyl methyl-2-methyl-4-nitroimidazole in the methylene dichloride, adds oleum and propylene oxide and obtains product in 20 ℃ of reactions, yield 14.5%.
5, In188550 and CN1442410A report is with 2-methyl-5-nitro imidazoles (1.5748mol) and propylene oxide (2.75mol) aluminum trichloride (anhydrous) (3.0mol) catalysis, with the anhydrous ethyl acetate is solvent, in the reaction back impouring dilute hydrochloric acid, reclaim unreacted 2-methyl-5-nitro imidazoles, alkalization back ethyl acetate extraction, the evaporate to dryness extraction liquid obtains product with water crystallization, yield 48.4%.
More than the shortcoming that exists of the preparation method of several secnidazoles be:
1. the used macro-corrosion of method 1 is strong, deleterious formic acid, and the operational requirement height, the postorder problem that reclaim under reduced pressure is handled is more.
2. method 2 is used expensive sodium borohydride and monochloroacetone, and step is long, yield low 3.62%; Method 3 also is that yield is low by 6.25%, is difficult to realize industrialization.
3. method 4 is used the strong oleum of corrodibility, operational hazards, and step is long, yield low 14.5%.
4. method 5 conditions need be anhydrous, to operation and equipment requirements height, realization of industrialization difficulty.Must use a large amount of ethyl acetate extractions after the reaction solution alkalization, and the ethyl acetate that reclaims can't reuse because of the water content height.
5. use more than in the method for propylene oxide, used propylene oxide boiling point very low (33.9 ℃), volatile, not easy to operate, and also relatively more dangerous.
Summary of the invention
The purpose of this invention is to provide a kind of can effectively reducing production costs, simplify the operation, improve the preparation method of the secnidazole of yield and quality product.
The present invention is the preparation method of secnidazole, with 2-methyl-5-nitro imidazoles and 1-chloro-2-propanol is raw material, it is characterized in that with excessive 1-chloro-2-propanol be solvent, feeds the exsiccant sour gas solid is all dissolved, reacting by heating, 1-chloro-2-propanol is reclaimed in distillation, regulates pH with sig water, and is cooled to 0 ℃, filter, reclaim unreacted 2-methyl-5-nitro imidazoles, filtrate transfers pH to alkalescence again, filters and obtains the secnidazole crude product.
Described sour gas can be hydrogen chloride gas.
Described temperature of reaction can be 85～95 ℃, and the reaction times is 6.0～7.5 hours.
Described sig water can be the sodium hydroxide solution of 1mol/L or the potassium hydroxide solution of 1mol/L.
Described twice usefulness sig water regulated in the pH operation, wherein can be for the first time and is adjusted to 3～4, can be for the second time and is adjusted to 10.
The mol ratio of described 2-methyl-5-nitro imidazoles and 1-chloro-2-propanol can be 1: 3.25～and 5.30.
Described secnidazole crude product used water recrystallization obtains the pure product of secnidazole.
The present invention compared with prior art has following outstanding advantage and positively effect:
1, reactions steps only one goes on foot, and has shortened the production cycle, has simplified operation; Overall yield of reaction brings up to 56～60% from bibliographical information below 50%.
2, compared with prior art, reduced raw-material a large amount of use, and served as solvent with excessive 1-chloro-2-propanol, reaction needn't add other solvents again, and aftertreatment also need not be used a large amount of organic solvent extractions; Unreacted 2-methyl-5-nitro imidazoles is applied mechanically through recyclable repetition the in washing back.
3,1-chloro-2-propanol boiling point higher relatively (126 ℃) has improved the security of producing.
4, secnidazole crude product water recrystallization obtains the pure product of secnidazole, and simple economy has been avoided with the dissolvent residual problem behind the organic solvent recrystallizations such as toluene.
Embodiment
The specific embodiment of the present invention will be described in detail in following examples, but following enforcement should not be construed as the scope of the present invention that limits.
Embodiment 1:
With the there-necked flask that 2-methyl-5-nitro imidazoles and 340.5ml (4.0mol) 1-chloro-2-propanol of 127.0g (1.0mol) joins 1000ml, stirring at room feeds the exsiccant hydrogen chloride gas to solid all till the dissolving.Be heated to 93 ℃ and be incubated 6.5 hours.Decompression steams 1-chloro-2-propanol 269.5g, recyclable applying mechanically after the Calcium Chloride Powder Anhydrous drying.The sodium hydroxide solution that adds 1mol/L in residuum is transferred pH to 3～4, and is cooled to 0 ℃.Filter, 2-methyl-5-nitro imidazoles is reclaimed in washing, and the oven dry back is 43.8g (recyclable applying mechanically).
In above-mentioned filtrate, continue to add the sodium hydroxide solution of 1mol/L and transfer pH=10, separate out solid, filter the secnidazole crude product.Crude product water recrystallization obtains pure product 107.5g, yield 58.1%, content 99.3%.
Embodiment 2:
With the there-necked flask that 2-methyl-5-nitro imidazoles and 447.0ml (5.25mol) 1-chloro-2-propanol of 127.0g (1.0mol) joins 1000ml, stirring at room feeds the exsiccant hydrogen chloride gas to solid all till the dissolving.Be heated to 90 ℃ and be incubated 6 hours.Decompression steams 1-chloro-2-propanol 363.7g, recyclable applying mechanically after the Calcium Chloride Powder Anhydrous drying.The sodium hydroxide solution that adds 1mol/L in residuum is transferred pH to 3～4, and is cooled to 0 ℃.Filter, 2-methyl-5-nitro imidazoles is reclaimed in washing, and the oven dry back is 44.6g (recyclable applying mechanically).
In above-mentioned filtrate, continue to add the sodium hydroxide solution of lmol/L and transfer pH=10, separate out solid, filter the secnidazole crude product.Crude product water recrystallization obtains pure product 109.3g, yield 59.1%, content 99.53%.
Embodiment 3:
With the there-necked flask that 2-methyl-5-nitro imidazoles and 293.7ml (3.45mol) 1-chloro-2-propanol of 127.0g (1.0mol) joins 1000ml, stirring at room feeds the exsiccant hydrogen chloride gas to solid all till the dissolving.Be heated to 88 ℃ and be incubated 7 hours.Decompression steams 1-chloro-2-propanol 224.6g, recyclable applying mechanically after the Calcium Chloride Powder Anhydrous drying.The sodium hydroxide solution that adds 1mol/L in residuum is transferred pH to 3～4, and is cooled to 0 ℃.Filter, 2-methyl-5-nitro imidazoles is reclaimed in washing, and the oven dry back is 45.9g (recyclable applying mechanically).
In above-mentioned filtrate, continue to add the sodium hydroxide solution of 1mol/L and transfer pH=10, separate out solid, filter the secnidazole crude product.Crude product water recrystallization obtains pure product 104.9g, yield 56.7%, content 99.45%.
Embodiment 4:
With the there-necked flask that the 2-methyl-5-nitro imidazoles and the new 2-methyl-5-nitro imidazoles of 63.5g of 63.5g recovery are put into 1000ml, add 340.5ml1-chloro-2-propyl alcohol, stirring at room is till feeding exsiccant hydrogen chloride gas to solid all dissolves.Be heated to 90 ℃ and be incubated 7 hours.Decompression steams 1-chloro-2-propanol 283.0g.The sodium hydroxide solution that adds 1mol/L in residuum is transferred pH to 3～4, and is cooled to 0 ℃.Filtration, 2-methyl-5-nitro imidazoles is reclaimed in washing, and the oven dry back is 47.7g (recovery set is used again).
In above-mentioned filtrate, continue to add the sodium hydroxide solution of 1mol/L and transfer pH=10, separate out solid, filter the secnidazole crude product.Crude product water recrystallization obtains pure product 103.8g, yield 56.1%, content 99.25%.
Embodiment 5:
The 1-chloro-2-propanol that the 2-methyl-5-nitro imidazoles of 127.0g (1.0mol) and 370.3ml (4.35mol) are reclaimed joins the there-necked flask of 1000ml, and stirring at room feeds the exsiccant hydrogen chloride gas to solid all till the dissolving.Be heated to 92 ℃ and be incubated 7.5 hours.Decompression steams 1-chloro-2-propanol 298.2g, and recovery set is used again after the Calcium Chloride Powder Anhydrous drying.The sodium hydroxide solution that adds 1mol/L in residuum is transferred pH to 3～4, and is cooled to 0 ℃.Filter, 2-methyl-5-nitro imidazoles is reclaimed in washing, and the oven dry back is 45.3g (recyclable applying mechanically).
In above-mentioned filtrate, continue to add the sodium hydroxide solution of 1mol/L and transfer pH=10, separate out solid, filter the secnidazole crude product.Crude product water recrystallization obtains pure product 104.0g, yield 56.2%, content 99.55%.
Claims (7)
1, a kind of preparation method of secnidazole, with 2-methyl-5-nitro imidazoles and 1-chloro-2-propanol is raw material, it is characterized in that with excessive 1-chloro-2-propanol be solvent, feeds the exsiccant sour gas solid is all dissolved, reacting by heating, 1-chloro-2-propanol is reclaimed in distillation, regulates pH with sig water, and is cooled to 0 ℃, filter, reclaim unreacted 2-methyl-5-nitro imidazoles, filtrate transfers pH to alkalescence again, filters and obtains the secnidazole crude product.
2, by the preparation method of the described secnidazole of claim 1, it is characterized in that described sour gas is a hydrogen chloride gas.
3, by the preparation method of the described secnidazole of claim 1, it is characterized in that described temperature of reaction is 85～95 ℃, the reaction times is 6.0～7.5 hours.
4, by the preparation method of the described secnidazole of claim 1, it is characterized in that described sig water is the sodium hydroxide solution of 1mol/L or the potassium hydroxide solution of 1mol/L.
5,, it is characterized in that in described twice usefulness sig water adjusting pH operation, wherein for the first time for being adjusted to 3～4, for the second time for being adjusted to 10 by the preparation method of claim 1 or 4 described secnidazoles.
6, by the preparation method of the described secnidazole of claim 1, the mol ratio that it is characterized in that described 2-methyl-5-nitro imidazoles and 1-chloro-2-propanol is 1: 3.25～5.30.
7, by the preparation method of the described secnidazole of claim 1, it is characterized in that described secnidazole crude product water recrystallization obtains the pure product of secnidazole.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103539745A (en) * | 2013-10-11 | 2014-01-29 | 黄冈赛康药业有限公司 | Preparation method of secnidazole |
| CN103772289A (en) * | 2014-01-03 | 2014-05-07 | 湖南迪诺制药有限公司 | Method for synthesizing secnidazole and secnidazole |
| CN114573511A (en) * | 2022-03-16 | 2022-06-03 | 安徽贝克制药股份有限公司 | Continuous synthesis method of metronidazole |
| CN114605332A (en) * | 2022-03-02 | 2022-06-10 | 潍坊富邦药业有限公司 | Preparation process of metronidazole |
| CN115677590A (en) * | 2022-11-07 | 2023-02-03 | 翔宇药业股份有限公司 | Preparation method of secnidazole |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2625999B1 (en) * | 1988-01-15 | 1990-06-08 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF HYDROXYALKYL-1 METHYL-2 NITRO-5 IMIDAZOLES |
| FR2659326A1 (en) * | 1990-03-12 | 1991-09-13 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF HYDROXYALKYL-1 NITRO-5 IMIDAZOLES. |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103539745A (en) * | 2013-10-11 | 2014-01-29 | 黄冈赛康药业有限公司 | Preparation method of secnidazole |
| CN103539745B (en) * | 2013-10-11 | 2015-09-02 | 黄冈赛康药业有限公司 | A kind of preparation method of secnidazole |
| CN103772289A (en) * | 2014-01-03 | 2014-05-07 | 湖南迪诺制药有限公司 | Method for synthesizing secnidazole and secnidazole |
| CN103772289B (en) * | 2014-01-03 | 2016-02-17 | 湖南迪诺制药有限公司 | The method of synthesis secnidazole and secnidazole |
| CN114605332A (en) * | 2022-03-02 | 2022-06-10 | 潍坊富邦药业有限公司 | Preparation process of metronidazole |
| CN114605332B (en) * | 2022-03-02 | 2024-03-12 | 潍坊富邦药业有限公司 | Preparation process of metronidazole |
| CN114573511A (en) * | 2022-03-16 | 2022-06-03 | 安徽贝克制药股份有限公司 | Continuous synthesis method of metronidazole |
| CN115677590A (en) * | 2022-11-07 | 2023-02-03 | 翔宇药业股份有限公司 | Preparation method of secnidazole |
| CN115677590B (en) * | 2022-11-07 | 2023-08-22 | 翔宇药业股份有限公司 | Preparation method of secnidazole |
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| CN100376559C (en) | 2008-03-26 |
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